Classes of Lipid Mediators and Their Effects on Vascular Inflammation in Atherosclerosis

Abstract

It is commonly believed that the inactivation of inflammation is mainly due to the decay or cessation of inducers. In reality, in connection with the development of atherosclerosis, spontaneous decay of inducers is not observed. It is now known that lipid mediators originating from polyunsaturated fatty acids (PUFAs), which are important constituents of all cell membranes, can act in the inflamed tissue and bring it to resolution. In fact, PUFAs, such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), are precursors to both pro-inflammatory and anti-inflammatory compounds. In this review, we describe the lipid mediators of vascular inflammation and resolution, and their biochemical activity. In addition, we highlight data from the literature that often show a worsening of atherosclerotic disease in subjects deficient in lipid mediators of inflammation resolution, and we also report on the anti-proteasic and anti-thrombotic properties of these same lipid mediators. It should be noted that despite promising data observed in both animal and in vitro studies, contradictory clinical results have been observed for omega-3 PUFAs. Many further studies will be required in order to clarify the observed conflicts, although lifestyle habits such as smoking or other biochemical factors may often influence the normal synthesis of lipid mediators of inflammation resolution.

Keywords: atherosclerosis; lipid mediators; polyunsaturated fatty acids; pro-resolving mediators; ω-3 fatty acid diet.

Figure 1

Molecular structure of the principal class 1 lipid mediators (on the left). On the right, the class 1 lipid mediators are divided according to their anti and pro cardiovascular risk properties.PGE2: prostaglandin E2; TXA2: thromboxane A2; 14-15 EET: 14-15 epoxyeicosatrienoic acid; LTB4: Leukotriene B4; LXA4: Lipoxin A4; 12(S)-HETE:12-hydroxyeicosatetraenoic acid; EP1,2,3, 4: prostaglandin Receptors.

Figure 2

Molecular structure of the principal class 2 lipid mediators (on the left). On the right, the class 2 lipid mediators are divided according to their anti- and pro-cardiovascular risk properties. PAF: Platelet activating factor; LPA: Lysophosphatidic acid; SP1: sphingosine-1-phosphate.

Figure 3

Molecular structure of the principal class 3 lipid mediators (on the left). On the right, the class 3 lipid mediators are divided according to their anti- and pro-cardiovascular risk properties. RvE: Resolvin E; RvD: Resolvin D; PD: Protectin; Maresin: MaR.

Figure 4

Simplified scheme of biochemical transition from inflammation to resolution. Pro-resolving lipid mediators enhance the clearance (efferocytosis) of apoptotic PNM by macrophages, blocking leukocyte recruitment and favoring tissue repair. PNM (circle in red colour): polymorphonuclear neutrophils; PNM (in gray colour):apoptotic polymorphonuclear neutrophils; stars in blue color: pro-resolving monocytes.